5-HT4 receptor antagonists

ABSTRACT

The invention provides the use of a compound of formula (I) ##STR1## wherein A, E, F, U, X, Y, Z, are as defined in the specification, or a pharmaceutically acceptable salt thereof, for the treatment of diarrhea predominant irritable bowel syndrome.

This application is a 371 of PCT/GB92/01419 filed Jul. 31, 1992.

This invention relates to the use of compounds as 5-HT₄ receptorantagonists in the treatment of gastrointestinal disorders, CNSdisorders and/or cardiovascular disorders, and to certain novelcompounds having 5-HT₄ receptor antagonist activity.

European Journal of Pharmacology 146 (1988), 187-188, andNaunyn-Schmiedeberg's Arch. Pharmacol. (1989) 340:403-410, describe anon classical 5-hydroxytryptamine receptor, now designated the 5-HT₄receptor, and that ICS 205-930, which is also a 5-HT₃ receptorantagonist, acts as an antagonist at this receptor.

PCT/GB91/00650 (SmithKline and French Laboratories Limited) describesthe use of cardiac 5-HT₄ receptor antagonists in the treatment of atrialarrhythmias and stroke.

Some 5-HT₃ receptor antagonists have been disclosed as of potential usein the treatment of certain aspects of irritable bowel syndrome [seeEP-A-189002 (Sandoz Limited) and EP-A-200444 (Beecham Group p.l.c)].

5-HT₃ receptor interactions which are of potential use in the treatmentof IBS are those associated either with the visceral pain and abnormalperception of sensation aspects of this disease, or they are related tothe ability of some 5-HT₃ receptor antagonists to cause constipation involunteers.

Some 5-HT₃ receptor antagonists have been disclosed as of potential usein the treatment of gastrointestinal disorders associated with upper gutmotility [see EP-A-226266 (Glaxo Group Ltd.) and EP-A-189002 (SandozLimited)]. 5-HT₃ receptor antagonists are also well known antiemetics,such as ondansetron, granisetron and tropisetron (see Drugs of theFuture 1989, 14 (9) p.875--F. D. King and G. J. Sanger).

EP-A-328200 and U.S. Pat. No. 4952587 (Merck Sharp & Dohme Ltd.)disclose a group of heterocyclic compounds which are described as usefulin the treatment of psychotic disorders (e.g. schizophrenia and mania);anxiety; alcohol or drug withdrawal; pain; gastric stasis; gastricdysfunction (such as occurs with dyspepsia, peptic ulcer, refluxoesophagitis and flatulence); migraine; nausea and vomiting andpresenile and senile dementia (also known as Alzheimer's disease andsenile dementia of the Alzheimer type respectively). Certain of thecompounds are described as acting on 5-HT₃ receptors and this isattributed in whole or in part, for the pharmacological activity ofthese compounds. J. Med. Chem. 1991, 34, 140-51 (Swain et. al.)describes these and other compounds and their properties as 5-HT₃receptor antagonists. J. Med. Chem. 1990, 33, 2715 describes a relatedgroup of 5-HT₃ receptor antagonists.

It has now been discovered that certain of the compounds embraced by thegeneral formulae disclosed therein, and related compounds, have 5-HT₄receptor antagonist properties, and are therefore of potential use inthe treatment of IBS or atrial arrhythmias and stroke.

The compounds of the present invention also have a potential use in thetreatment of CNS disorders such as anxiety and/or migraine, in thetreatment of upper gut motility disorders and as antiemetics.

When used herein `treatment` includes prophylaxis as appropriate.

The invention therefore provides the use of a compound of formula (I) ora pharmaceutically acceptable salt thereof: ##STR2## wherein the dottedcircle represents one or two double bonds in any position in the5-membered ting; X, Y and Z independently represent oxygen, sulphur,nitrogen or carbon, provided that at least one of X, Y and Z representsoxygen, sulphur or nitrogen; U represents nitrogen or carbon;

A represents a group of formula (II): ##STR3## in which: R¹ representshydrogen, hydroxy, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy,hydroxy (C1-6)alkyl, halogen, amino, cyano, --CONR⁶ R⁷ or --SO₂ NR⁶ R⁷,in which R⁶ and R⁷ independently represents hydrogen, C₁₋₆ alkyl, C₂₋₆alkenyl or C₂₋₆ alkynyl;

R² represents hydrogen, halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy or C₁₋₆alkylcarbonyl;

V represents nitrogen,

    --CH or --C--

and

W represents oxygen, sulphur or ##STR4## in which R⁸ representshydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl;

E represents a straight or branched alkylene or alkenylene chaincontaining from 1 to 5 carbon atoms and optionally containing an --O--,--S--, --NH-- or --Nalkyl-- linkage; and

F represents:

a) a non-aromatic azacyclic ring system or a non-aromatic azabicyclicring system having carbon bridgehead(s); or.

b) a group of formula --NR^(a) R^(b) wherein one of R^(a) and R^(b) ishydrogen or C₁₋₆ alkyl and the other is hydrogen, C₁₋₁₀ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl or aryl(C₁₋₆)alkyl;

in the manufacture of a medicament for use as a 5-HT₄ receptorantagonist.

In the above formula (II):

V preferably represents N or CH;

W preferably represents NR⁸ ;

R¹ preferably represents H; and

R² preferably represents --CH--.

The group A in formula (I) is therefore preferably as indole or indazoleof formula (IIA): ##STR5## wherein V is N, CH or CHR² and R¹ are asdefined for formula (I) above, and are preferably as described forformula (II) above.

The group A in formula (I) may also be replaced by a substituted phenylmoiety, as described in formula (III) of EP-A-189002, for example asdescribed in Example 2 hereinafter.

Suitable examples of A, X, Y, Z, E and F are as described inEP-A-328200, or as in the following Examples.

Examples of alkyl or alkyl containing groups include C₁, C₂, C₃, C₄, C₅,C₆, C₇, C₈, C₉, C₁₀, C₁₁ or C₁₂ branched, straight chained or cyclicalkyl, as appropriate. C₁₋₄ alkyl groups include methyl, ethyl n- andiso-propyl, n-, iso-, sec- and tert-butyl. Cyclic alkyl includescyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl andcyclooctyl. Alkenyl includes all suitable values including E and Zforms.

Aryl includes phenyl and naphthyl.

Halo includes fluoro, chloro, bromo and iodo.

Suitable examples of F are as described in EP-A-328200, i.e. thosehaving an R⁵ substituent wherein the group E is optionally attachedthrough R⁵. Other examples of F of interest are those described for thecompounds of the Examples hereinafter.

Suitable examples of compounds of formula (I) include that described inExample 21 of EP-A-328200,1-methyl-3-[5-(2-(1-piperidyl)ethyl)-1,2,4-oxadiazol-3-yl]indole. Othersuitable examples of compounds of formula (I) are described in theExamples hereinafter.

The pharmaceutically acceptable salts of the compounds of the formula(I) include acid addition salts with conventional acids such ashydrochloric, hydrobromic, boric, phosphoric, sulphuric acids andpharmaceutically acceptable organic acids such as acetic, tartaric,maleic, citric, succinic, benzoic, ascorbic, methanesulphonic, α-ketoglutaric, α-glycerophosphoric, and glucose-1-phosphoric acids.

Examples of pharmaceutically acceptable salts include quaternaryderivatives of the compounds of formula (I) such as the compoundsquaternised by compounds R_(x) -T wherein R_(x) is C₁₋₆ alkyl,phenyl-C₁₋₆ alkyl or C₅₋₇ cycloalkyl, and T is a radical correspondingto an anion of an acid. Suitable examples of R_(x) include methyl, ethyland n- and iso-propyl; and benzyl and phenethyl. Suitable examples oftinclude halide such as chloride, bromide and iodide.

Examples of pharmaceutically acceptable salts also include internalsalts such as N-oxides.

The compounds of the formula (I), their pharmaceutically acceptablesalts, (including quaternary derivatives and N-oxides) may also formpharmaceutically acceptable solvates, such as hydrates, which areincluded wherever a compound of formula (I) or a salt thereof is hereinreferred to.

Some of the compounds of formula (I) have at least one asymmetric centreand exist as more than one stereoisomeric form. The invention extends toeach of these forms and to mixtures thereof including racemates.

The compounds of the present invention are 5-HT₄ receptor antagonistsand it is thus believed may generally be used in the treatment orprophylaxis of gastrointestinal disorders, cardiovascular disorders andCNS disorders.

They are of potential interest in the treatment of irritable bowelsyndrome (IBS), in particular the diarrhoea aspects of IBS, i.e., thesecompounds block the ability of 5-HT to stimulate gut motility viaactivation of enteric neurones. In animal models of IBS, this can beconveniently measured as a reduction of the rate of defaecation. Theyare also of potential use in the treatment of urinary incontinence whichis often associated with IBS.

They may also be of potential use in other gastrointestinal disorders,such as those associated with upper gut motility, and as antiemetics. Inparticular, they are of potential use in the treatment of the nausea andgastric symptoms of gastro-oesophageal reflux disease and dyspepsia.Antiemetic activity is determined in known animal models ofcytotoxic-agent/radiation induced emesis.

Specific cardiac 5-HT₄ receptor antagonists which prevent atrialfibrillation and other atrial arrhythmias associated with 5-HT, wouldalso be expected to reduce occurrence of stroke (see A. J. Kaumann 1990,Naumyn-Schmiedeberg's Arch. Pharmacol. 342, 619-622, for appropriateanimal test method).

It is believed that platelet-derived 5-HT induces atrial arrhythmiaswhich encourage atrial fibrillation and atrial disorders are associatedwith symptomatic cerebral and sytemic embolism. Cerebral embolism is themost common cause of ischaemic stroke and the heart the most commonsource of embolic material. Of particular concern is the frequency ofembolism associated with atrial fibrillation.

Anxiolytic activity is likely to be effected via the hippocampus (Dumuiset al 1988, Mol Pharmacol., 34, 880-887). Activity may be demonstratedin standard animal models, the social interaction test and the X-mazetest.

Migraine sufferers often undergo situations of anxiety and emotionalstress that precede the appearance of headache (Sachs, 1985, Migraine,Pan Books, London). It has also been observed that during and within 48hours of a migraine attack, cyclic AMP levels are considerably increasedin the cerebrospinal fluid (Welch et al., 1976, Headache 16, 160-167).It is believed that a migraine, including the prodomal phase and theassociated increased levels of cyclic AMP are related to stimulation of5-HT₄ receptors, and hence that administration of a 5-HT₄ antagonist isof potential benefit in relieving a migraine attack.

5-HT₄ receptor antagonist activity may be identified according tostandard methods, such as those described hereinafter.

Examples of 5-HT₄ receptor antagonists include ICS 205-930(tropisetron), which is described in the above mentioned patentreferences, R 50 595 (Janssen), which is described in FR76530 and Eur.J.Pharmacol., 181 119-125 (1990), and SDZ 205-557, which is described byK. H. Buchheit and R. Gamse in Naunyn-Schmiedeberg's Arch. Pharmacol.,343 (Suppl.), R101 (1991).

In one aspect, the compound of formula (I) is a more potent antagonistat 5-HT₄ receptors than at 5-HT₃ receptors.

Preferably, the 5-HT₄ receptor antagonist of formula (I) is insubstantially pure pharmaceutically acceptable form.

The compounds of formula (I) may be prepared as described in EP-A-328200and U.S. Pat. No. 4,952,587, and in the Examples and Descriptionshereinafter.

The administration of the compound may be by enteral such as oral,rectal or nasal, sublingual, transdermal or parenteral administration.

An amount effective to treat the disorder hereinbefore described dependson the usual factors such as the nature and severity of the disorderbeing treated and the weight of the mammal. However, a trait dose willnormally contain 0.1 to 50 mg for example 0.5 to 10 mg, of the activeingredient. Unit doses will normally be administered once or more thanonce a day, for example 2, 3, or 4 times a day, more usually 1 to 3times a day, such that the total daily dose is normally in the range,for a 70 kg adult of 0.1 to 50 mg, for example 0.1 to 5 mg, that is inthe range of approximately 0.00 1 to 1 mg/kg/day, more usually 0.005 to0.2 mg/kg/day.

For oral or parenteral administration, it is greatly preferred that thecompound is administered in the form of a unit-dose composition, such asa unit dose oral or parenteral composition.

Such compositions are prepared by admixture and are suitably adapted fororal or parenteral administration, and as such may be in the form oftablets, capsules, oral liquid preparations, powders, granules,lozenges, reconstitutable powders, injectable and infusable solutions orsuspensions or suppositories.

Tablets and capsules for oral administration are usually presented in aunit dose, and contain conventional excipients such as binding agents,fillers, diluents, tabletting agents, lubricants, disintegrants,colourants, flavourings, and wetting agents. The tablets may be coatedaccording to well known methods in the art.

Suitable fillers for use include cellulose, mannitol, lactose and othersimilar agents. Suitable disintegrants include starch,polyvinylpyrrolidone and starch derivatives such as sodium starchglycollate. Suitable lubricants include, for example, magnesiumstearate. Suitable pharmaceutically acceptable wetting agents includesodium lauryl sulphate.

These solid oral compositions may be prepared by conventional methods ofblending, filling or tabletting. Repeated blending operations may beused to distribute the active agent throughout those compositionsemploying large quantities of fillers. Such operations are, of course,conventional in the art.

Oral liquid preparations may be in the form of, for example, aqueous oroily suspensions, solutions, emulsions, syrups, or elixirs, or may bepresented as a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives such as suspending agents, for example sorbitol,syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel or hydrogenareal edible fats,emulsifying agents, for example lecithin, sorbitan monooleate, oracacia; non-aqueous vehicles (which may include edible oils), forexample, almond oil, fractionated coconut oil, oily esters such asesters of glycerine, propylene glycol, or ethyl alcohol; preservatives,for example methyl or propyl p-hydroxybenzoate or sorbic acid, and ifdesired conventional flavouring or colouring agents.

Oral formulations also include conventional sustained releaseformulations, such as tablets or granules having an enteric coating.

For parenteral administration, fluid unit dose forms are preparedcontaining the 5-HT₄ receptor antagonist and a sterile vehicle. Thecompound, depending on the vehicle and the concentration, can be eithersuspended or dissolved. Parenteral solutions are normally prepared bydissolving the compound in a vehicle and filter sterilising beforefilling into a suitable vial or ampoule and sealing. Advantageously,adjuvants such as a local anaesthetic, preservatives and bufferingagents are also dissolved in the vehicle. To enhance the stability, thecomposition can be frozen after filling into the vial and the waterremoved under vacuum.

Parenteral suspensions are prepared in substantially the same mannerexcept that the compound is suspended in the vehicle instead of beingdissolved and sterilised by exposure to ethylene oxide before suspendingin the sterile vehicle. Advantageously, a surfactant or wetting agent isincluded in the composition to facilitate uniform distribution of thecompound of the invention.

As is common practice, the compositions will usually be accompanied bywritten or printed directions for use in the treatment concerned.

The present invention also provides the use of a compound of formula(I), or a pharmaceutically acceptable salt thereof in the manufacture ofa medicament for use in the treatment and/or prophylaxis of irritablebowel syndrome, gastro-oesphageal reflux disease, dyspepsia, atrialarrhythmias and stroke, anxiety and/or migraine. Such treatment and/orprophylaxis may be carried out as hereinbefore described.

The present invention also provides a method of treatment and/orprophylaxis of irritable bowel syndrome, gastro-oesphageal refluxdisease, dyspepsia, atrial arrhythmias and stroke, anxiety and/ormigraine in mammals, including humans, which method comprisesadministering to the mammal in need of such treatment and/orprophylaxis, an effective and/or prophylactic amount of a compound offormula (I) or a pharmaceutically acceptable salt thereof.

The present invention further provides a pharmaceutical composition foruse in the treatment and/or prophylaxis of irritable bowel syndrome,gastro-oesphageal reflux disease, dyspepsia, atrial arrhythmias andstroke, anxiety and/or migraine which comprises a compound of formula(I), or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier. Such compositions may be preparedin the manner as hereinbefore described.

The following Examples illustrate compounds for use in the invention,the following Descriptions illustrate the preparation of intermediates.

    ______________________________________                                         ##STR6##                                                                      ##STR7##                                                                     Example A         n      F                                                    ______________________________________                                        E1      A.sup.1   3                                                                                     ##STR8##                                            E2      A.sup.1 (Me)                                                                            0                                                                                     ##STR9##                                            E3      A.sup.1 (Me)                                                                            1                                                                                     ##STR10##                                           E4      A.sup.1 (Me)                                                                            0                                                                                     ##STR11##                                           E5      A.sup.1 (Me)                                                                            1                                                                                     ##STR12##                                           E6      A.sup.1 (Me)                                                                            1                                                                                     ##STR13##                                           E7      A.sup.1 (Me)                                                                            1                                                                                     ##STR14##                                           E8      A.sup.1 (Me)                                                                            1                                                                                     ##STR15##                                           E9      A.sup.1 (Me)                                                                            0                                                                                     ##STR16##                                           E10     A.sup.1 (Me)                                                                            1                                                                                     ##STR17##                                           E11     A.sup.1 (Me)                                                                            1                                                                                     ##STR18##                                           E12     A.sup.1 (Me)                                                                            4                                                                                     ##STR19##                                           E13     A.sup.1 (Et)                                                                            3                                                                                     ##STR20##                                           E14     A.sup.2   3                                                                                     ##STR21##                                           E15     A.sup.1 (Me)                                                                            2                                                                                     ##STR22##                                           E16     A.sup.1 (Me)                                                                            2                                                                                     ##STR23##                                           E17     A.sup.1 (Me)                                                                            2                                                                                     ##STR24##                                           E18     A.sup.1 (Me)                                                                            2                                                                                     ##STR25##                                           E19     A.sup.1 (Me)                                                                            2                                                                                     ##STR26##                                           E20     A.sup.1 (Me)                                                                            2                                                                                     ##STR27##                                           E21     A.sup.1 (Me)                                                                            2                                                                                     ##STR28##                                           E22     A.sup.1 (Me)                                                                            2                                                                                     ##STR29##                                           E23     A.sup.1 (Me)                                                                            2                                                                                     ##STR30##                                           E24     A.sup.1 (Me)                                                                            2                                                                                     ##STR31##                                           E25     A.sup.1 (Me)                                                                            2                                                                                     ##STR32##                                           E26     A.sup.1 (Me)                                                                            2                                                                                     ##STR33##                                           E27     A.sup.1 (Me)                                                                            2                                                                                     ##STR34##                                           E28     A.sup.1 (Me)                                                                            2                                                                                     ##STR35##                                           E29     A.sup.1 (Me)                                                                            2                                                                                     ##STR36##                                           ______________________________________                                    

EXAMPLE 15-[3-(N-Methylbutylamino)propyl]-3-[1-methyl-1H-indol-3-yl]-1,2,4-oxadiazole(E1)

1-Methyl-1H-indole-3-carboxamide oxime (C. J. Swain et al, J.Med. Chem,1991, 34, 147)(0.250 g, 1.33 mmol) was dissolved in dry THF (8 ml) withstirring and treated with ground 4A° molecular sieves (1 g), undernitrogen. After 30 minutes sodium hydride (80% dispersion in mineraloil) (0.044 g, 1.46 mmol) was added. The mixture was then heated toreflux, after 30 minutes, the mixture was allowed to cool momentarily,and a solution of ethyl-4-N-methylbutylaminobutyrate (0.293 g, 1.46mmol) in dry THF (2 ml) was added. The mixture was then heated toreflux. After 6 h, the reaction mixture was allowed to cool, and wasthen filtered. The filter pad was then washed with THF (2×) and thefiltrate evaporated under reduced pressure. The residue was thenpurified by silica-gel chromatography, eluting with ethylacetate/methanol 20:1 to afford the title compound as a colourless oil(0.243 g, 56%), which was converted to its hydrochloride salt, m.pt,174°-175° C.

¹ H NMR (250 MHz, CD₃ SOCD₃)

δ: 10.8 (s, 1H), 8.12 (s, 1H), 8.03 (d, J=8 Hz, 1H), 7.58 (d, J=8 Hz,1H), 7.20-7.37 (m, 2H), 3.90 (s, 3H), 2.96-3.32 (m, 6H), 2.77 (s, 3H),2.17-2.35 (m, 2H), 1.61-1.78 (m, 2H), 1.28-1.41 (m, 2H), 0.92 (t, J=6Hz, 3H).

EXAMPLES 2 TO 12

The following compounds were prepared analogously:

5-[N-Butyl-4-piperidyl]-3-(1-methylindol-3-yl)-1,2,4-oxadiazole (E2)

mp 69°-70° C.

¹ H NMR (250 MHz, CDCl₃) (free base)

δ: 8.24 (dd, J=8 and 1 Hz, 1H), 7.80 (s, 1H), 7.22-7.42 (m, 3H), 3.89(s, 3H), 2.93-3.10 (m, 3H), 2.38 (t, J=8 Hz, 2H), 2.00-2.23 (m, 6H),1.45-1.60 (m, 2H), 1.22-1.41 (m, 2H), 0.92 (t, J=6 Hz, 3H).

5N-Butyl-4-piperidylmethyl]-3-(1-methylindol-3-yl)-1,2,4-oxadiazole (E3)

mp 182°-183° C. (HCl salt)

¹ H NMR (250 MHz, CDCl₃) (free base)

δ: 8.22 (dd, J=8 and 1 Hz, 1H), 7.80 (s, 1H), 7.24-7.42 (m, 3H), 3.89(s, 3H), 2.95 (m, 2H), 2.89 (d, J=8 Hz, 2H) 2.32 (t, J=8 Hz, 2H),1.73-2.02 (m, 5H), 1.42-1.58 (m, 2H), 1.21-1.42 (m, 2H), 0.92 (t, J=6Hz, 3H).

5-[N-Butyl-3-piperidyl]-3-(1-methylindol-3-yl)-1,2,4-oxadiazole (E4)

mp 219°-220° C. (HCl salt)

¹ H NMR (270 MHz, CDCl₃) (HCl salt)

δ: 12.80-12.98 br (s, 1H), 8.20 (dd, J=8 and 1 Hz, 1H), 7.79 (s, 1H),7.24-7.42 (m, 3H), 4.21 (m, 1H), 3.97 (m, 1H), 3.89 (s, 3H), 3.62 (m,1H), 2.92-3.08 (m, 2H), 2.48-2.79 (m, 3H), 1.32-1.52 (m, 2H), 1.00 (t,J=6 Hz, 3H).

5-[N-Butyl-3-piperidylmethyl]-3-(1-methylindol-3-yl]-1,2,4-oxadiazole(E5)

mp 195°-198° C. (HCl salt)

¹ H NMR (250 MHz, CD₃ SOCD₃)

δ: 10.80 br (s, 1H), 8.15 (s, 1H), 8.02 (d, J=8 Hz, 1H), 7.58 (d, J=8Hz, 1H), 7.20-7.38 (m, 2H), 3.90 (s, 3H), 3.55 (m, 1H), 2.92-3.10 (m,4H), 2.68-2.85 (m, 2H), 1.61-1.92 (m, 6H), 1.13-1.40 (m, 4H), 0.90 (t,J=6 Hz, 3H).

5-[N-Butyl-2-piperidylmethyl]-3-(1-methylindol-3-yl)-1,2,4-oxadiazole(E6)

mp 65°-68° C. (oxalate salt)

¹ H NMR (250 MHz, CDCl₃) (free base)

δ: 8.21 (dd, J=8 and 1 Hz, 1H), 7.80 (s, 1H), 7.24-7.40 (m, 3H), 3.89(s, 3H), 3.00-3.30 (m, 2H), 2.40-2.80 (m, 2H), 1.40-1.80 (m, 9H),1.22-1.38 (m, 2H), 0.92 (t, J=6 Hz, 3H).

5-[Indolizidin-2-ylmethyl]-3(1-methylindol-3-yl)-1,2,4-oxadiazole (E7)

Higher RF isomer

mp 215°-216° C. (HCl salt)

¹ H NMR (250 MHz, CDCl₃) (free base)

δ: 8.22 (dd, J=8 and 1 Hz, 1H), 7.79 (s, 1H), 7.24-7.42 (m, 3H), 3.89(s, 3H), 3.05 (m, 3H), 2.93 (dd, J=10 and 1 Hz, 1H), 2.52 (m, 1H), 2.40(t, J=8 Hz, 1H), 2.18 (m, 1H), 1.71-2.03 (m, 5H), 1.52-1.70 (m, 1H),1.17-1.32 (m, 3H).

Lower RF isomer

mp 215°-218° C. (HCl salt)(free base)

¹ H NMR (250 MHz, CDCl₃)

δ: 8.22 (dd, J=8 and 1 Hz, 1H), 7.79 (s, 1H), 7.20-7.40 (m, 3H), 3.89(s, 3H), 3.38 (t, J=8 Hz, 1H), 3.08 (m, 1H), 2.94 (m, 2H), 2.80 (m, 1H),1.50-2.05 (m, 9H), 1.18-1.41 (m, 2H).

5-(Quinolizidin-2-ylmethyl)-3-(1-methylindol-3-yl)-1,2,4-oxadiazole (E8)

mp 173°-175° C. (HCl salt)

¹ H NMR (250 MHz, CD₃ SOCD₃) (HCl salt)

δ: 10.4 (s, 1H), 8.14 (s, 1H), 8.03 (d, J=8 Hz, 1H), 7.58 (d, J=8 Hz,1H), 7.20-7.38 (m, 2H), 3.89 (s, 3H), 3.30 (m, 1H), 2.80-3.15 (m, 5H),2.20 (br s, 1H), 1.40-2.00 (m, 10H).

5-(Quinolizidin-2-ylmethylene)-3-(methylindol-3-yl)-1,2,4-oxadiazole(E9)

Higher RF isomer

mp 226°-227° C. (HCl salt)

¹ H NMR (250 MHz, CD₃ SOCD₃) (HCl salt)

δ: 11.20 (br, s, 1H), 8.18 (s, 1H), 8.05 (d, J=8 Hz, 1H), 7.60 (d, J=8Hz, 1H), 7.20-7.38 (m, 2H), 6.60 (s, 1H), 4.05 (d, J=11 Hz, 1H), 3.89(s, 3H), 3.55 (m, 1H), 2.70-3.25 (m, 6H), 1.60-2.00 (m, 6H), 1.40-1.60(m, 1H).

Lower RF isomer

mp 227°-228° C. (HCl salt)

¹ H NMR (250 MHz, CD₃ SOCD₃) (HCl salt)

δ: 11.15 (br, s, 1H), 8.20 (s, 1H), 8.06 (d, J=8 Hz, 1H), 7.60 (d, J=8Hz, 1H), 7.20-7.38 (m, 2H), 6.61 (s, 1H), 4.08 (d, J=10 Hz, 1H), 3.89(s, 3H), 3.58 (m, 1H), 3.40 (m, 1H), 2.54-3.30 (m, 6H), 1.80-2.10 (m,5H), 1.40-1.60 (m, 1H).

5[2-(N-Methylcyclohexylmethylamino)ethyl]-3(1-methylindol-3-yl)-1,2,4-oxadiazole(E10)

mp 162°-163° C. (HCl salt)

¹ H NMR (250 MHz, CDCl₃) (free base)

δ: 8.27 (dd, J=8 and 1 Hz, 1H), 7.85 (s, 1H), 7.30-7.47 (m, 3H), 3.98(s, 2H), 3.89 (s, 3H), 2.44 (s, 3H), 2.33 (d, J=8 Hz, 2H), 1.50-1.90 (m,5H), 1.10-1.40 (m, 4H), 0.82-1.00 (m, 2H).

5-(N-Methylbutylaminomethyl)-3-(1-methylindol-3-yl)-1,2,4-oxadiazole(E11)

mp 182°-183° C. (HCl salt)

¹ H NMR (250 MHz, CDCl₃) (free base)

δ: 8.24 (dd, J=8 and 1 Hz, 1H), 7.82 (s, 1H), 7.29-7.42 (m, 3H), 3.95(s, 2H), 3.89 (s, 3H), 2.55 (t, J=6 Hz, 2H) 2.42 (s, 3H), 1.50-1.62 (m,2H), 1.25-1.47 (m, 2H), 0.94 (t, J=6 Hz, 3H).

5-[4-(N-Methylbutylamino)butyl]-3-(1-methylindol-3-yl)-1,2,4-oxadiazole(E12)

mp 130°-132° C. (HCl salt)

¹ H NMR (250 MHz, CDCl₃) (free base)

δ: 8.22 (dd, J=8 and 1 Hz, 1H), 7.79 (s, 1H), 7.25-7.41 (m, 3H), 3.88(s, 3H), 2.98 (t, J=6 Hz, 2H), 2.30-2.44 (m, 4H), 2.20 (s, 3H), 1.90 (m,2H), 1.21-1.70 (m, 6H), 0.92 (t, J=6 Hz, 3H).

EXAMPLE 135-[(3-(Piperidino)propyl)]-3-(1-ethyl-1H-indol-3-yl)-1,2,4-oxadiazole(E13)

1-Ethylindole-3-ylcarboxamide oxime (200 mg, 0.98 mmol, prepared by thegeneral method of EP-A-328200) was dissolved in anhydrous THF (4 ml)containing 4-A° powdered molecular sieves (300 mg). The mixture wasstirred for 30 mins., sodium hydride (80% dispersion in oil) (40 mg, 1.3mmol) was added and the mixture was heated at 60° C. for 20 min. It wasthen cooled to RT and a solution of methyl-4-piperidinyl butyrate (364mg, 1.98 mmol) in THF (2 mol) was added. The resulting mixture washeated at reflux for 1 hr., cooled, filtered and the filtrateconcentrated under vacuum. The residue was purified by columnchromatography to give the product (210 mg).

mp 190°-91° C. (oxalate salt).

EXAMPLE 145-[3-(Piperidino)propyl]-3-(2-methoxy-4-amino-5-chlorophen-1-yl)-1,2,4-oxadiazole(E14)

2-Methoxy-4-amino-5-chlorobenzamide-oxime (D1)(0.250 g, 1.16 mmol) wasdissolved in dry THF (8 ml) and treated with ground 4A° molecular sieves(1 g). The mixture was then stirred at room temperature for 1/2 h,before Nail (80% disp. in mineral oil) (0.035 g, 1.16 mmol) was added.The mixture was then heated to reflux. After 1/2 h the reaction mixturewas allowed to cool momentarily, and methyl-4-piperidinyl-butyrate(0.242 g, 1.22 mmol)in dry THF (3 ml) was added. Reflux was thenmaintained for a further 4 h. The reaction mixture was then allowed tocool, and was filtered. The filter pad was washed with THF (2×), and thefiltrate was evaporated under reduced pressure to give a yellow solid.The solid was purified by silica-gel chromatography using EtOAc:MeOH98/2-95/5 as eluant to give the title compound as a white solid (0.270g, 66%). m.pt 112°-114° C. (from CH₂ Cl.sub. 2 /Petrol)

¹ H NMR (270 MHz, CDCl₃) (free base)

δ: 7.93 (s, 1H), 6.40 (s, 1H), 4.37 (s, 2H), 3.90 (s, 3H), 2.93 (t, J=6Hz, 2H), 2.30-2.48 (m, 6H), 1.98-2.12 (m, 2H), 1.50-1.62 (m, 4H),1.35-1.49 (m, 2H).

EXAMPLE 155-[(4-Methyl-piperidino)ethyl]-3-(1-methyl-1-H-indol-3-yl)-1,2,4-oxadiazole(E15)

5-Ethenyl-3-(1-methyl-1-H-indol-3-yl)-1,2,4-oxadiazole (D2)(0.0254 g,1.13 mmol) was dissolved in methanol (5 ml) and 4-methyl piperidine(0.167 ml, 1.69 mmol) was added. The mixture was left standing at roomtemperature for 16 hours, before being evaporated under reduced pressureto give a colourless oil, which was purified by silica-gelchromatography, eluting with ethyl acetate to afford the title compoundas a colourless oil that crystallised on standing. The material was thenconverted to its hydrochloride salt, mp 192°-192° C.

¹ H NMR (250 MHz, CD₃ SOCD₃) (HCl salt)

δ: 10.9 br (s, 1h), 8.13 (s, 1H), 8.03 (d, J=8 Hz, 1H), 7.58 (d, J=8 Hz,1H), 7.21-7.38 (m, 2H), 3.89 (s, 3H), 3.48-3.70 (m, 6H), 2.90-3.10 (m,2H), 1.72-1.90 (m, 2H), 1.43-1.70 (m, 3H), 0.90 (d, J=6 Hz, 3H).

EXAMPLES 16 TO 29

The following compounds were prepared analogously:

5-[2-(Thiomorpholino)ethyl]-3-(1-methylindol-3-yl)-1,2,4-oxadiazole(E16)

mp 121°-122° C. (free base)

¹ H NMR (250 MHz, CDCl₃) (free base)

δ: 8.22 (dd, J=8 and 1 Hz, 1H), 7.80 (s, 1H), 7.27-7.42 (m, 3H), 3.89(s, 3H), 3.13 (m, 2H), 3.00 (m, 2H), 2.85 (m, 2H), 2,69 (m, 2H).

5-[2-(Hexamethyleneimino)ethyl]-3-(1-methylindol-3-yl)-1,2,4-oxadiazole(E17)

mp 173°-175° C. (HCl salt)

¹ H NMR (250 MHz, CD₃ SOCD₃) (HCl salt)

δ: 11.04 br (s, 1H), 8.12 (s, 1H), 8.03 (d, J=8 Hz, 1H), 7.58 (d, J=8Hz, 1H), 7.20-7.38 (m, 2H), 3.89 (s, 3H), 3.60 (s, 4H), 3.45 (m, 2H),3.22 (m, 2H), 1.76-1.92 (m, 4H), 1.50-1.75 (m, 4H).

5[2-(N-Methylcyclohexylamino)ethyl]-3-(1-methylindol-3-yl)-1,2,4-oxadiazole(E18)

mp 162°-163° C. (HCl salt)

¹ H NMR (250 MHz, CD₃ SOCD₃) (HCl salt)

δ: 10.95 br (s, 1H), 8.22 (s, 1H), 8.04 (d, J=8 Hz, 1H), 7.59 (d, J=8Hz, 1H), 7.20-7.38 (m, 2H), 3.79 (s, 3H), 3.40-3.80 (m, 4H), 3.22-3.40(m, 1H), 2.80 (d, J=6 Hz, 3H), 2.10 (m, 2H), 1.82 (m, 2H), 1.08 (m, 6H).

5[2-((R)-(-)-1-Cyclohexylethylamino)ethyl]-3-(1-methylindol-3-yl)-1,2,4-oxadiazole(E19)

mp 206°-207° C. (HCl salt)

¹ H NMR (250 MHz, CD₃ SOCD₃) (HCl salt)

δ: 9.30 br (s, 1H), 8.88 br (s, 1H), 8.12 (s, 1H), 8.05 (d, J=8 Hz, 1H),7.60 (d, J=8 Hz, 1H), 7.20-7.38 (m, 2H), 3.89 (s, 3H), 3.40-3.58 (m,4H), 3.10-3.25 (m, 1H), 1.60-1.88 (m, 6H), 0.98-1.38 (m, 8H).

5[2-((S)-(+)-1-Cyclohexylethylamino)ethyl]-3(1-methylindol-3-yl)-1,2,4-oxadiazole(E20)

mp 205°-206° C.

¹ H NMR--as given for E19

5[2-((R)-(+)-α-Methylbenzylamino)ethyl]-3-(1-methylindol-3-yl]-1,2,4-oxadiazole(E21)

mp 128°-129° C. (free base)

¹ H NMR (250 MHz, CDCl₃) (free base)

δ: 8.22 (dd, J=8 and 1 Hz, 1H), 7.80 (s, 1H), 7.20-7.42 (m, 8H), 3.90(s, 3H), 3.88 (q, J=6 Hz, 1H), 2.92-3.12 (m, 4H), 1.80 (s, 1H), 1.39 (d,J=6 Hz, 3H).

5[2-(S)-(-)-α-Methylbenzylamino)ethyl]-3-(1-methylindol-3-yl)-1,2,4-oxadiazole(E22)

mp 126°-127° C.

¹ H NMR (CDCl₃)--as given for E21

5-[2-(Cyclohexylethylamino)ethyl]-3-(1-methylindol-3-yl)-1,2,4-oxadiazole(E23)

mp 204°-205° C. (HCl salt)

¹ H NMR (250 MHz, CD₃ SOCD₃) (HCl salt)

δ: 9.23 (s, 2H), 8.13 (s, 1H), 8.03 (d, J=8 Hz, 1H), 7.58 (d, J=8 Hz,1H), 7.20-7.38 (m, 2H), 3.90 (s, 3H), 3.40-3.58 (m, 4H), 2.85 (d, J=6Hz, 2H), 1.60-1.90 (m, 6H), 0.90-1.33 (m, 3H), 0.89-1.08 (m, 2H).

5-[2-(3,3-Dimethylbutylamino)ethyl]-3-(1-methylindol-3-yl)-1,2,4-oxadiazole(E24)

mp 215°-217° C. (HCl salt)

¹ H NMR (250 MHz, CD₃ SOCD₃) (HCl salt)

δ: 9.33 (s, 2H), S.13 (s, 1H), 8.04 (d, J=8 Hz, 1H), 7.58 (d, J=8 Hz,1H), 7.20-7.38 (m, 2H), 3.89 (s, 3H), 3.48 (m, 4H), 3.00 (m, 2H), 1.58(m, 2H), 0.90 (s, 9H).

5-[2-(1,3-Dimethylbutylamino)ethyl]-3-(1-methylindol-3-yl)-1,2,4-oxadiazole (E25)

mp 182°-183° C. (HCl salt)

¹ H NMR (250 MHz CD₃ SOCD₃) (HCl salt)

δ: 9.30 (s, 2H), 8.12 (s, 1H), 8.05 (d, J=6 Hz, 1H), 7.60 (d, J=6 Hz,1H), 7.20-7.38 (m, 2H), 3.89 (s, 3H), 3.50 (m, 4H), 3.30 (m, 1H),1.52-1.80 (m, 2H), 1.42 (m, 1H), 1.28 (d, J=6 Hz, 3H), 0.93 (d, J=6 Hz,3H), 0.88 (d, J=6 Hz, 3H).

5-[2-(N-Methyl-N-benzylamino)ethyl]-3-(1-methylindol-3-yl)-1,2,4-oxadiazole(E26)

mp 156°-158° C. (HCl salt)

¹ H NMR (250 MHz, CD₃ SOCD₃) (HCl salt)

δ: 11.4 (s, 1H), 8.13 (s, 1H), 8.03 (d, J=8 Hz, 1H), 7.67 (m, 2H) 7.58(d, J=8 Hz, 1H), 7.48 (m, 3H), 7.20-7.38 (m, 2H), 4.52 (m, 1H), 4.37(dd, J15 and 5 Hz, 1H), 3.89 (s, 3H), 3.50-3.78 (m, 4H), 2.75 (d, J=5Hz, 3H).

5-[2-(Benzylamino)ethyl]-3-(1-methylindol-3-yl)-1,2,4-oxadiazole (E27)

mp 207°-207° C. (HCl salt)

¹ H NMR (250 MHz, CD₃ SOCD₃) (HCl salt)

δ: 9.75 (s, 2H), 8.13 (s, 1H), 8.04 (d, J=8 Hz, 1H), 7.56-7.68 (m, 3H),7.42-7.52 (m, 3H), 7.20-7.38 (m, 2H), 4.26 (s, 2H), 3.40-3.55 (m, 4H).

cis-5-[2-(4-Methylcyclohexylamino)ethyl]-(1-methylindol-3-yl)-1,2,4-oxadiazole(E28)

mp 214°-216° C. (HCl salt)

¹ H NMR (400 MHz, CD₃ SOCD₃) (HCl salt)

δ: 9.27 br (s, 2H), 8.11 (s, 1H), 8.05 (d, J=8 Hz, 1H), 7.57 (d, J=8 Hz,1H), 7.21-7.35 (m, 2H), 3.89 (s, 3H), 3.41-3.54 (m, 4H), 3.15-3.25 (m,1H), 1.64-1.85 (m, 5H), 1.43-1.54 (m, 4H), 0.92 (d, J=6 Hz, 3H).

trans-5-[2-(4-Methylcyclohexylamino)ethyl]-3-(1-methylindol-3-yl)-1,2,4-oxadiazole(E29)

mp 206°-208° C. (HCl salt)

¹ H NMR (400 MHz, CD₃ SOCD₃) (HCl salt)

δ: 9.23 br (s, 2H), 8.12 (s, 1H), 8.04 (d, J=8 Hz, 1H), 7.58 (d, J=8 Hz,1H), 7.22-7.38 (m, 3H), 3.89 (s, 3H), 3.32 (s, 4H), 2.99-3.10 (m, 1H),2.10 (m, 2H), 1.74 (m, 1H), 1.25-1.50 (m, 3H), 0.90-1.02 (m, 4H), 0.87(d, J=6 Hz, 3H).

EXAMPLES 30 TO 36

    ______________________________________                                         ##STR37##                                                                    Example   X       Y      Z     U    E                                         ______________________________________                                        E30       N       N      N     N    (CH.sub.2).sub.2                          E31       N       S      N     C    S(CH.sub.2).sub.2                         E32       N       C      N     N    (CH.sub.2).sub.2                          E33       N       N      O     C    (CH.sub.2).sub.2                          E34       O       N      N     C    (CH.sub.2).sub.2                          E35       N       O      N     C    NH(CH.sub.2).sub.2                        E36       C       S      N     C    (CH.sub.2).sub.2                          ______________________________________                                    

EXAMPLE 30 3-(2-Piperidylethyl)-5-(1-methyl-1H-indol-3-yl)tetrazole(E30)

3-(1-Acetylpiperidyl)-5-(1-methyl-1H-indol-3-yl) tetrazole (0.080 g,0.247 mmol) (D3) was dissolved in dry THF (2 ml) and added to 1Mborane-tetrahydrofuran complex (0.741 ml, 0.741 mmol). The mixture washeated to reflux under N₂. After 1 h, a further amount of 1Mborane-tetrahydrofuran complex (0.741 ml, 0.741 mmol) was added. Themixture was then heated under reflux for a further 0.5 h, before beingallowed to cool. 4M HCl in methanol (1 ml) was then added and themixture then heated under reflux for 1 h, allowed to cool, andevaporated under reduced pressure to give an oily solid which wastreated with 10% NaOH. The aqueous mixture was then extracted with CHCl₃(2×). The combined organic layers were dried (Na₂ SO₄) and evaporated togive the title compound as a colourless oil (0.065 g, 85%), whichcrystallised on standing, and was converted to its hydrochloride salt.

mp (HCl salt) 228°-230° C.

¹ H NMR (250 MHz, CD₃ SOCD₃) (HCl salt)

δ: 11.15 (1H,s)0.60(1H, d, J=8 Hz), 7.30(2H,m), 5.32(2H, t, J=5 Hz),3.90(3H), s), 3.80(2H,m), 3.50(2H,m), 3.00(2H,m), 1.90-1.60(5H,m),1.50-1.30(1H,m)

EXAMPLE 315(1-Thio-2-(piperidino)ethyl)-3-[1-methyl-1-H-indol-3-yl]-1,2,4-thiadiazole(E31)

5-Thio-3-[1-methyl-1H-indol-3-yl]-1,2,4-thiadiazole (0.112 g, 0.453mmol) (D4) was dissolved in ethanol (4 ml) and sodium hydride (80%)(0.014 g, 0.475 mmol) was added with stirring:1-(2-Chloroethyl)piperidine hydrochloride was then dissolved in ethanol(2 ml) containing sodium hydride (80%)(0.014 g, 0.475 mmol). Theresultant solution was then added to the solution of the thiol. Themixture was then heated under reflux, under N₂. After 4 h, the reactionmixture was allowed to cool and was evaporated under reduced pressure togive an orange solid, which was partitioned between CHCl₃ and water. Theaqueous layer was then extracted with CHCl₃ and the combined organiclayers were dried (Na₂ SO₄) and evaporated under reduced pressure togive a yellow oil (0.130 g). The oil was then purified by silica-gelchromatography (2:1 pentane EtOAc as eluant) to give the title compoundas a colourless oil (0.110 g, 68%), which was converted to itshydrochloride salt.

mp (HCl salt) 197°-200° C.

¹ H NMR (250 MHz, CDCl₃) (free base)

δ: 8.45(1H,m), 7.90(1H,s), 7.40-7.20(3H,m), 3.89(3H,s), 3.50(2H, t, J=6Hz), 2.82(2H, t, J=6 Hz), 2.54(4H,m), 1.65(4H,m), 1.47(2H,m).

EXAMPLE 32 1-[2-Piperidylethyl]-3(1-methyl-1H-indol-3-yl)-1,2,4-triazolehydrochloride (E32)

1-[1-Acetylpiperidyl]-3-(1-methyl-1H-indol-3-yl) 1,2,4-triazole (0.080g, 0.248 mmol)(D5) was dissolved in dry THF (3 ml) and added to 1Mborane-tetrahydrofuran complex (1.24 ml, 1.24 mmol). The mixture wasthen heated to reflux under N₂ with stirring. After 2.5 h the mixturewas allowed to cool and 4M HCl in methanol was added. The reaction wasthen heated to reflux for 1 h before being allowed to cool, and was thenevaporated under reduced pressure. The residue was then partitionedbetween CHCl₃ and 10% sodium hydroxide solution. The aqueous layer wasthen extracted with CHCl₃ and the combined organic layers were dried(Na₂ SO₄) and evaporated under reduced pressure to give a colourlessoil, which was purified by silica-gel chromatography (EtOAc:MeOH 20:1)to give the title compound as a colourless oil (0.025 g 33%), which wasconverted to its hydrochloride salt.

mp. 195°-197° C.

¹ H NMR (250 MHz, CDCl₃) (free base)

δ: 8.34(1H, d, J=8 Hz), 8.18(1H,s), 7.73(1H,s), 7.38-7.20(3H,m),7.38-7.20(3H,m), 4.28(2H, t, J=6 Hz), 3.85(3H,s), 2.82(2H, t, J=6 Hz),2.45(4H,m), 1.56-1.38(6H,m)

EXAMPLE 335-[2-(Piperidyl)ethyl]-3-(1-methyl-1H-indol-3-yl)-1,3,4-oxadiazole (E33)

1-[3-(1-Piperidyl)propionyl]-2-[3-carbonyl-1-methyl-1H-indol-3-yl]hydrazide (0.280 g, 0.854 mmol)(D6) wasdissolved in POCl₃ (4 ml) and heated to reflux with stirring. After 0.75h, the reaction mixture was allowed to cool and was poured carefullyinto water (15 ml). Solid sodium bicarbonate was then added to themixture until pH 8 was reached. The resultant yellow sludge was thenextracted with CH₂ Cl₂ (3×). The combined organic layers were then dried(Na₂ SO₄) and evaporated under reduced pressure to give a yellow oil,which was purified by silica-gel chromatography (EtOAc:MeOH 10:1 aseluant) to give the rifle compound as a colourless oil (0.148 g, 56%),which was converted to its hydrochloride salt.

mp (HCl salt) 222°-223° C.

¹ H NMR (250 MHz, CD₃ SOCD₃) (HCl salt)

δ: 10.82(1H,s). 8.20(1H,s), 8.10(1H, d, J=8 Hz), 7.60(1H, d, J=8 Hz),7.30(2H,m), 3.92(3H,s), 3.55(6H,m), 3.10-2.90(2H,m), 1.90-1.65(5H,m),1.50-1.30(1H,m)

EXAMPLE 343-[2-Piperidylethyl]-5-[1-methyl-1H-indol-3-yl]-1,2,4-oxadiazole (E34)

3-(1-Piperidyl)propionamide oxime (0.903 g, 5.28 mmol)(D7) was dissolvedin dry THF (40 ml) containing ground 4A molecular sieves (3.0 g). After0.5 h sodium hydride (0.346 g, 5.76 mmol) was added and the mixture washeated to reflux under N₂. Meanwhile (1-methyl-1H-indol-3-yl carboxylicacid) (J. Org. Chem. 1958 23, 1096)(0.840 g, 4.80 mmol) was suspended in(CH₂ Cl₂ (30 ml) and oxalyl chloride was added (0.628 g, 7.20 mmol),followed by a drop of dry DMF. The mixture was then stirred at roomtemp. for 1.5 h, before being evaporated under reduced pressure anddried in vacuo to give the crude acid chloride, which was then dissolvedin dry THF (10 ml) and added to the refluxing solution of the amidoximesalt (after 1.5 h). After 3 h the reaction mixture was allowed to cool,was filtered and the filtrate evaporated under reduced pressure to givea brown oil, which was purified by silica-gel chromatography (2% MeOH inCHCl₃ as eluant) to give the title compound as a colourless oil (0.546g, 37%) which was converted to its hydrochloride salt.

mp (HCl salt ) 174°-176° C.

¹ H NMR (250 MHz, CD₃ SOCD₃) (HCl salt)

δ: 11.00(1H,s), 8.40(1H,s), 8.12(1H,d, J=8 Hz), 7.63(1H, d, J=8 Hz),7.40-7.20(2H,m), 3.92(3H,s), 3.60-3.35(6H,m), 3.00(2H,m),1.95-1.55(5H,m), 1.40(1H,m)

EXAMPLE 355[1-Amino-2-(piperidyl)ethyl]-3-[1-methyl-1H-indol-3-yl]-1,2,4-oxadiazole(E35)

5-Trichloromethyl-3-[1-methyl-1H-indol-3-yl]-1,2,4-oxadiazole (0.100 g,0.316 mmol) (D8) was dissolved with stirring in 1-(2-aminoethyl)piperidine (0.8 ml) and heated to 120° C. After 0.5 h, the reactionmixture was allowed to cool and was partitioned between EtOAc and water.The organic layer was then washed with water (1×), dried (Na₂ SO₄) andevaporated under reduced pressure to give a yellow oil which waspurified by silica gel chromatography (10% MeOH in EtOAc as eluant) togive the title compound as a colourless oil that crystallised onstanding (0.095 g, 93%).

mp 146°-147° C. from CH₂ Cl₂ /petrol

¹ H NMR (250 MHz, CDCl₃)

δ: 8.20(1H,dd, J=8 and 1 Hz), 7.70(1H,s), 7.40-7.20(3H,m), 6.10(1H,s),3.89(3H,s), 3.54(2H,q, J=6 Hz), 2.60(2H, t, J=6 Hz), 2.45(4H,s),1.60(4H,m), 1.48(2H,m)

EXAMPLE 36 5-[1H-Indol-3-yl]-2-[2-piperidylethyl]-1,3-thiazole (E36)

The title compound was prepared from 3-bromoacetylindole and1-(3-amino-3-thioxopropyl)piperidine according to the method of RosenT., Nagel A. A. et al, J. Med. Chem 1990, 33, 2715-2720.

mp 155°-7° C.

¹ H NMR (250 MHz, CD₃ SOCD₃ (HCl salt)

δ: 11.4 (1H,s), 8.07(1H,d), 7.87(1H,d), 7.70(1H,s), 7.43(1H,d),7.14(2H,m), 3.55(6H,m), 2.9-3.2(2H,m), 1.7-1.95(5H,m), 1.3-1.5(1H,m)

DESCRIPTIONS Description 1 (intermediate for Example 14)2-Methoxy-4-amino-5 chlorobenzamide--Oxime

Sodium (0.245 g, 10.62 mmol) was dissolved in methanol (10 ml).Hydroxylamine hydrochloride (0.738 g, 10.62 mmol) in methanol (10 ml)was then added to the stirred solution. The mixture was then stirred atroom temperature for 1/2 h, before being filtered. The filter pad wasthen washed with methanol (˜10 ml) and the filtrate was treated with2-methoxy-4-amino-5-chlorobenzonitrile (A. Morimoto and Y. Saito, Jap.patent 71 03, 368, C.Abs 74, 111779h). The mixture was then heated toreflux with stirring. After 24 h, the reaction mixture was allowed tocool, and was then evaporated under reduced pressure to give a yellowsolid. The solid was then recrystallised from methanol. The resultingpale yellow solid was then dried in vacuo to give the title compound(D1) (0.462 g, 40%). m.pt. 178°-181° C.

¹ H NMR (250 MHz, (CD₃ SOCD₃)

δ: 9.28 (s, 1H), 7.20 (s, 1H), 6.48 (s, 1H), 5.58 (s, 2H), 5.48 (s, 2H),3.70 (s, 3H).

Description 2 (intermediate for Example 15)5-Ethenyl-3-(1-methyl-1H-indol-3-yl)-1,2,4-oxadiazole

1-Methyl-1H-indole-3 carboxamide oxime (C. J. Swain et al, J Med Chem,1991, 34, 147) (0.500 g, 2.64 mmol) was dissolved in dry THF (20 ml)with stirring, and treated with ground 4A molecular sieves (1.5 g) undernitrogen. After 30 minutes sodium hydride (80% dispersion in mineraloil) (0.087 g, 2.91 mmol) was added. The mixture was then heated toreflux. After 30 minutes the mixture was allowed to cool momentarily anda methyl acrylate (0.475 ml, 5.28 mmol) was added. The mixture was thenheated to reflux for a further 3 hours. The reaction mixture was thenallowed to cool and was filtered. The filter pad was then washed withTHF (2×). The filtrate was then evaporated under reduced pressure. Theresidue was purified by silica-gel chromatography eluting with pentaneEtOAc 3:1 to afford the title compound (D2) as a colourless oil thatcrystallised on standing rapt 53°-55° C.

¹ H NMR (250 MHz, CDCl₃)

δ: 8.25 (m, 1H), 7.80 (s, 1H), 7.26-7.42 (m, 3H), 6.70-6.85 (dd, J=18,11 Hz), 6.56 (d, J=18 Hz, 1H), 5.98 (d, J=11 Hz, 1H), 3.79 (s, 3H).

Description 3 (intermediate for Example 30)

a) 5-(1-Methyl-1H-indol-3-yl)tetrazole

3-Cyano(1-methyl-1H-indole) (J. Med. Chem. 199, 34, 147) (0.500 g, 3.21mmol) was dissolved in dry DMF (4 ml) and treated with ammonium chloride(0.214 g, 4.01 mmol) and sodium azide (0.260 g, 4.01 mmol). The mixturewas then heated to reflux with stirring. After 26 h, the reactionmixture was allowed to cool and was evaporated under reduced pressure togive a brown oil. Water (15 ml) was added to this residue whereupon itsolidified. The mixture was made strongly basic with sodium hydroxidesolution and then extracted with diethyl ether. The aqueous layer wasthen treated with activated charcoal and heated on a water bath for 10minutes. The mixture was then filtered and the filtrate acidified with5M HCl to pH₄. The resulting brown precipitate was then filtered off anddried in vacuo to give the title compound (0.125 g, 20%) as a pale brownsolid.

¹ H NMR (250 MHz, CD₃ SOCD₃)

δ: 8.24(1H,dd, J=7 and 1 Hz), 8.08(1H, s), 7.60(1H, dd, J=7 and 1 Hz),7.30(2H, m)3.91(3H,s).

b) 3-(1-Acetylpiperidyl)-5(1-methyl-1H-indol-3-yl)tetrazole

5-(1-Methyl-1H-indol-3-yl)tetrazole (0.080 g, 0.402 mmol) was dissolvedin dry THF (5 ml) and treated with sodium hydride (80%) (0.014 g, 0.441mmol). When effervescence had ceased, 1-(bromoacetyl)piperidine (Bull.Soc. Chim. France 1964 5, 1063) (0.093 g, 0.422 mmol) in dry THF (2 ml)was added. After 1 h, a further amound of 1-(bromoacetyl)piperidine(0.047 g, 0.211 mmol) in dry THF (1 ml) was added. After a further 2 h,the reaction mixture was evaporated under reduced pressure to give abrown solid which was partitioned between CHCl₃ and water. The organiclayer was washed with NaHCO₃ solution, and the combined aqueous layerswere extracted with CHCl₃. The combined organic layers were then dried(Na₂ SO₄) and evaporated to give an off white foam which was dried invacuo and then purified by silica-gel chromatography (pentane: EtOAc 1:1as eluant) to give the title compound (D3 ) as a white solid (0.080 g,61%)

¹ H NMR (250 MHz, CDCl₃)

δ: 8.32(1H, dd. J=7 and 1 Hz), 7.88(1H,s), 7.32(3H, m), 5.53(2H,s),3.89(3H,s), 3.60(2H,t, J=5 Hz), 3.48(2H, t, J=8 Hz), 1.62(6H, m)

Description 4 (intermediate for Example 31)5-Thio-3-[1-methyl(-1H-indol-3-yl]-1,2,4-thiadiazole

3-[1-Methyl(1H-indol-3-yl]carboxamide oxime (J. Med. Chem. 199, 34, 147)was dissolved in dry THF (10 ml). Ground 4A molecular sieves (1.0 g)were then added and the mixture was stirred at room temp. Sodium hydride(80%) (0.052 g, 1.746 mmol) was then added and the mixture heated toreflux for 0.5 h. Carbon disulphide (0.286 ml, 4.76 mmol) was thenadded. Reflux was maintained for a further 2 h, before the reactionmixture was allowed to cool. The reaction mixture was then filtered andthe filtrate evaporated under reduced pressure. The resultant brown oilwas then purified by silica-gel chromatography (1:1 Pentane:EtOAc aseluant) to give the title compound as a yellow solid (0.080 g, 20%)(D4)

¹ H NMR (250 MHz, CD₃ SOCD₃)

δ: 8.30(1H, s), 8.20(1H,d, J=7 Hz), 7.58(1H, d, J=7 Hz), 7.28(2H,m),3.89(3H,s).

Description 5 (intermediate for Example 32)

a) 3-(1-Methyl-1H-indol-3-yl)1,2,4-triazole

Methyl(1-methyl-1H-indol-3-yl)imidate hydrochloride (J. Chem. Soc.Perkin. Trans. 1, 1990, 3183) was dissolved with stirring in drymethanol (10 ml) and treated with trimethylamine (0.123 ml, 1.069 mmol).The reaction mixture was then stirred at room temperature for 0.25 h,then formyl hydrazide (0.064 g, 1.069 mmol) was added. The mixture washeated to reflux and after 7 h the reaction mixture was allowed to cooland was evaporated under reduced pressure. The solid residue was thendissolved in formic acid (10 ml) and refluxed for 0.75 h. The reactionmixture was allowed to cool and then evaporated under reduced pressureand purified by silica-gel chromatography (EtOAc as eluant) to give thetitle compound as a colourless oil (0.055 g, 31%).

¹ H NMR (250 MHz, CDCl₃)

δ: 8.20 (1H, d, J=8 Hz), 8.15(1H,s), 7.60(1H,s), 7.32-7.15(3H,m),3.65(3H,s)

b) 1-[1-Acetylpiperidyl]-3-(1-methyl-1H-indol-3-yl)-1,2,4-triazole

3-(1-Methyl-1H-indol-3-yl)-1,2,4-triazole (0.190 g, 0.960 mmol) wasdissolved with stirring in dry THF (5 ml) and was treated with sodiumhydride (80%) (0.032 g, 1.05 mmol), followed by1-(bromoacetyl)piperidine (Bull. Soc, Chim. Fr. 1964, 5, 1063-9) (0.232g, 1.05 mmol) in dry THF (1 ml). After 4 h, the reaction mixture wasevaporated under reduced pressure and partitioned between EtOAc andwater. The organic layer was then dried (Na₂ SO₄) and evaporated underreduced pressure to give a yellow oil, which was purified by silica-gelchromatography (EtOAc→EtOAc:MeOH 100:1 as eluant) to give the titlecompound (D5b) as a white solid (0.080 g, 26%).

¹ H NMR (250 MHz, CDCl₃)

δ: 8.32(1H, dd, J=7 and 1 Hz), 8.21(1H,s), 7.40-7.20(3H,m), 5.06(2H, s)3.85(3H, s), 3.62-3.48(4H,m), 1.72-1.50(6H,m).

Description 6 (intermediate for Example 33)

1-[3-(1-Piperidyl)propionyl]-2-[3-carbonyl-1-methyl(-1H-indol-3-yl]hydrazid

1-Methyl-1H-indole-3-carboxylic acid (J. Org. Chem 1958 23 1096-1097),(0.614 g, 3.51 mmol) was suspended in dry CH₂ Cl₂ (15 ml) and treatedwith oxalyl chloride (0.459 ml, 5.26 mmol) with stirring, followed by adrop of DMF. After 0.75 h, the reaction mixture was evaporated underreduced pressure and dried in vacuo. The orange solid produced was thenredissolved in CH₂ Cl₂ (15 ml), triethylamine (0.512 ml, 3.86 mmol) wasthen added, followed by [3(1-piperidyl)propionyl]hydrazide (SeancesAcad. Sci. Ser. C. (1976) 282 (17) 857-60)(0,600 g, 3.51 mmol) in CH₂Cl₂ (4 ml). The mixture was stirred at room temperature overnight, andwashed with sodium bicarbonate solution (2×). The organic layer wasdried (Na₂ SO₄) and evaporated to give a cream solid, which was purifiedby silica gel chromatography (20% EtOH in CHCl₃ as eluant) to give thetitle compound (D6) (0.280 g, 24%) as a white solid.

¹ H NMR (250 MHz, CDCl₃)

δ: 9.22(1H,s), 8.10(1H,m), 7.72(1H,s), 7.30-7.10(3H,m), 3.60(3H,s),2.70(3H,m), 2.55(4H,m), 1.75(4H,m), 1.60-1.40(2H,m)

Description 7 (intermediate for Example 34)

3(1-Piperidyl)propionamide oxime

Sodium (1.09 g, 0.047 mol) was added carefully to methanol (10 ml) underN₂ with stirring. When all the sodium had dissolved, a solution ofhydroxylamine hydrochloride (3.29 g, 0.047 mol) in methanol (30 ml) wasadded slowly. The mixture was then stirred at room temp for 1/2 h beforebeing filtered. The filtrate was then treated with3(1-piperidyl)propionitrile (Chem. Abs. 47, 9906) (3.27 g, 0.024 mol)and the mixture heated to reflux. After 7.5 h the reaction mixture wasallowed to cool and was then evaporated under reduced pressure. Theresidue was then triturated with diethylether to give a white solidwhich was filtered off and dried in vacuo the title compound (3.30 g,82%) (D7)

¹ H NMR (250 MHz, CD₃ SOCD₃)

δ: 9.0(1H,s), 5.60(2H,s), 3.05-2.85(6H,m), 2.42(2H, t, J=6 Hz),1.70(4H,m), 1.50(2H,m)

Description 8 (intermediate for Example 35)5-Trichloromethyl-3-[1-methyl-1H-indol-3-yl]-1,2,4-oxadiazole

1-Methyl-1H-indole-3-carboxamide oxime (J. Med. Chem. 1991 34, 147)(2.00 g, 0.011 mol) was added to trichloroacetic anydride (20 ml) withice cooling and stirring. The mixture was then stirred at roomtemperature. After 2.5 h, the reaction mixture was poured onto a mixtureof ethyl acetate and aqueous sodium bicarbonate. The aqueous layer wasthen extracted with ethyl acetate and the combined organic layers weredried (Na₂ SO₄) and evaporated under reduced pressure to give a yellowsolid which was purified by silica-gel chromatography (Pentane: EtOAc10:1) to give the title compound as a cream coloured solid (1.29 g,39%).

¹ H NMR (400 MHz,CDCl₃)

δ: 8.20(1H,dd, J=8 and 1 Hz), 7.88(1H,s), 7.40-7.20(3H,m), 3.89(3H,s)

5-HT₄ RECEPTOR ANTAGONIST ACTIVITY

1) Guinea pig colon

Male guinea-pigs, weighing 250-400 g are used. Longitudinalmuscle-myenteric plexus preparations, approximately 3 cm long, areobtained from the distal colon region. These are suspended under a 0.5 gload in isolated tissue baths containing Krebs solution bubbled with 5%CO₂ in O₂ and maintained at 37° C. In all experiments, the Krebssolution also contains methiothepin 10⁻⁷ M and granisetron 10⁻⁶ M toblock effects at 5-HT₁, 5-HT₂ and 5-HT₃ receptors.

After construction of a simple concentration-response curve with 5-HT,using 30s contact times and a 15rain dosing cycle, a concentration of5-HT is selected so as to obtain a contraction of the muscleapproximately 40-70% maximum(10⁻⁹ M approx). The tissue is thenalternately dosed every 15 min with this concentration of 5-HT and thenwith an approximately equi-effective concentration of the nicotinereceptor stimulant, dimethylphenylpiperazinium (DMPP). After obtainingconsistent responses to both 5-HT and DMPP, increasing concentrations ofa putative 5-HT₄ receptor antagonist are then added to the bathingsolution. The effects of this compound are then determined as apercentage reduction of the contractions evoked by 5-HT or by DMPP. Fromthis data, pIC₅₀ values are determined, being defined as the -logconcentration of antagonist which reduces the contraction by 50%. Acompound which reduces the response to 5-HT but not to DMPP is believedto act as a 5-HT₄ receptor antagonist.

The compound of Example 21 of EP-A-328200 had a pIC₅₀ of 7.3.

Compounds were generally active in the range of concentrations of theorder of pIC₅₀ =6 or more, E1 and E3 showing particularly good activity.

2) Piglet Atria

Compounds were tested in the piglet spontaneous beating screen(Naunyn-Schmiedeberg's Arch. Pharmacol 342, 619-622). pK_(B) (-log₁₀K_(B)) value for the compound of Example 21 of EP-A-328200 was 7.6.

3) Rat oesophagus

Rat oesophageal tunica muscularis mucosae is set up according to Baxteret. al. Naunyn-Schmiedeberg's Arch. Pharmacol., 343, 439-446 (1991). Theinner smooth muscle tube of the muscularis mucosae is isolated andmounted for isometric tension recording in oxygenated (95% O₂ /5% CO₂)Tyrodes solution at 37° C. All experiments are performed in pargylinepretreated preparations (100 μM for 15 rain followed by washout) and inthe presence of cocaine (30 μM). Relaxant responses to 5-HT are obtainedafter pre-contracting the oesophagus tissue with carbachol (3μM).

4) 5-HT-induced motility in dog gastric pouch

Compounds are tested for inhibition in the in vivo method described in"Stimulation of canine motility by BRL 24924, a new gastric prokineticagent", Bermudez et al, J. Gastrointestinal Motility, 2(4), 281-286.

We claim:
 1. A method of treating diarrhea predominant irritable bowelsyndrome, which comprises administering a compound selectedfrom:5-[3-(N-methylbutylamino)propyl]-3-[1-methyl-1H-indol-3-yl]-1,2,4-oxadiazole,5[N-butyl-4-piperidylmethyl]-3-(1-methylindol-3-yl)-1,2,4-oxadiazole,and5[2-((R)-(+)-α-methylbenzylamino)ethyl]-3-(1-methylindol-3-yl]-1,2,4-oxadiazole.